The Odyssey of Therapeutic Vaccines for HIV

Introduction

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In the earliest days after the discovery of HIV in the mid-1980s, uncertainty reigned regarding how the immune system responded to the virus. Initially, it was thought that the time between HIV infection and the development of severe immuno-deficiency and disease represented a period of viral inactivity or latency. In this context, it seemed logical to propose that perhaps vaccination could be used to bolster immune response to HIV and thus delay or even prevent the development of illness.

But the first efforts toward this goal quickly mired therapeutic vaccine research in controversy, casting an initial pall across the field that was compounded by the failure of any candidate to show significant efficacy. Additionally, the scientific rationale for the approach evolved as more was learned about the pathogenesis of HIV infection and the types of immune responses that may be effective -- and ineffective -- at controlling the virus. After a period in which enthusiasm regarding the prospects for therapeutic vaccines waned, the recent resurgence in interest in research aiming to cure HIV infection has offered new reasons to pursue their development.

History

The controversy that attended the earliest research into therapeutic vaccination began in the mid-1980s when a French scientist named Daniel Zagury obtained a vaccinia virus from the National Institutes of Health that had been modified to include several components from HIV, and proceeded to test it in both HIV-infected and -uninfected individuals in Paris and Zaire without appropriate regulatory approval (the vaccinia construct had been created only for the purpose of conducting studies in animals). Several of the HIV-infected participants died, and this fact was omitted from published reports about the experiments (which instead attempted to suggest the vaccine was efficacious).

Following quickly on the heels of this debacle were two more woeful contretemps relating to therapeutic HIV vaccine candidates. A company named MicroGeneSys created a vaccine containing the HIV gp160 protein, and Robert Redfield, a scientist with the Walter Reed Army Institute of Research, conducted trials in people with HIV. At the International AIDS Conference in Amsterdam in 1992, Redfield claimed the preliminary results were encouraging but quickly came under fire for overstating the findings. The situation was aggravated by a successful attempt to secure a $20 million congressional appropriation specifically to conduct an efficacy trial of the vaccine, bypassing normal research review mechanisms (this money was ultimately redirected after Redfield's initial analysis was shown to be unreliable).

The International AIDS Conference in Berlin in 1993 was the site of the third blow to the credibility of therapeutic HIV vaccine research. A great deal of enthusiasm had attended Jonas Salk's venture into the field in the late 1980s, when he described the development of a vaccine comprising a whole-killed HIV isolate that was intended to be tested as a preventive and therapeutic vaccine. Due to regulatory concerns about the safety of killed vaccines in HIV-negative individuals, Salk focused on therapeutic studies. Results were hotly anticipated and due to be presented in Berlin, but they were not debuted at the conference itself, but rather at a news conference; this decision fostered distrust and anger among attendees before the data were even described. The unimpressive outcomes of the trials, which Salk and the Immune Response Corporation (the company set up to produce the vaccine) tried to spin positively, served as the final insult.

As these disasters piled up, scientific advances were also undermining the original rationale for the approach. The notion that HIV was latent during the asymptomatic phase of the infection was overturned by data showing that the virus was constantly replicating, and that this replication was accompanied by the ongoing proliferation and death of CD4 T cells. Improvements in tools for evaluating immune responses revealed that there is a massive specific response to HIV that, in most individuals, is unable to control viral replication, leading to a situation where the immune system essentially flails away at the virus throughout the course of infection. Furthermore, CD4 T cells responding to HIV (HIV-specific CD4 T cells) were shown to be preferentially infected, contributing to their poor functionality and inability to deliver appropriate help to the other vital components of an antiviral immune response: CD8 T cells, whose primary task is to recognize and kill virus-infected cells, and B cells, which generate antibodies that -- when effective -- glom onto free floating viral particles and prevent them infecting new cells. These findings seriously called into question the idea that adding more HIV antigens into the mix via therapeutic vaccination -- when the virus itself was failing to induce protective immunity -- would be beneficial. While research did not entirely come to a halt, it was not viewed as a priority, and hopes for a successful therapeutic vaccine faded.

A Second Try

The burgeoning success of triple combinations of antiretroviral drugs (ART) in the mid-1990s might have been expected to further erode interest in therapeutic vaccines, but it ultimately led to a mild revival in interest, for two main reasons. Firstly, the drugs were clearly imperfect in terms of safety and side effects, leading to interest in approaches that might allow intermittent or delayed use of ART. Secondly, the profound suppression of HIV replication mediated by ART facilitated reconstitution of the immune system, and some scientists speculated that this may offer an opportunity to use vaccines to induce new HIV-specific immune responses that could develop (or "mature" in vaccine parlance) without interference from HIV because the drugs were keeping the virus at bay.

These ideas prompted a slew of new trials combining a variety of vaccine candidates with ART. These candidates included Salk's whole-killed vaccine (now called Remune), attenuated viruses used as vectors to deliver HIV antigens (such as the canarypox-based ALVAC and cowpox-based MVA), and "naked DNA" constructs that deliver the genetic code for making vaccine antigens into cells. Data were generated showing that HIV-specific CD4 and CD8 T-cell responses could be induced in individuals with suppressed viral loads, and in some cases laboratory tests suggested that the functionality of these T-cell responses was markedly superior to those present prior to vaccination. But the harder question to answer was whether these apparent immunologic effects of therapeutic vaccines could be translated into a measurable health benefit.

Remune underwent testing in a large, randomized, placebo-controlled phase III trial that evaluated whether vaccination reduced morbidity and mortality in people with HIV, the vast majority of whom were on ART. No significant differences in the incidence of opportunistic infections or deaths were seen, but the interpretation of the results was complicated by the fact that the standard of care for ART evolved from dual- to triple therapy while the trial was ongoing, and that there were -- happily -- very few endpoints in both the Remune and placebo arms. Because the effectiveness of ART made it essentially impossible to demonstrate an additional benefit from therapeutic vaccination, alternative study designs became more common. There were two main approaches. The first was to immunize individuals on ART and then evaluate the effects on CD4 T-cell levels and viral load during an ART interruption (in hopes of allowing extended breaks from ART). The second was to administer therapeutic vaccines to individuals with early infection prior to ART initiation (in hopes of being able to show a delay in reaching CD4 thresholds indicating a need for ART). Data from these types of trials occasionally hinted that receipt of therapeutic vaccines was associated with better preservation of CD4 T-cell counts and slightly lower viral loads during ART interruptions, although at least one trial of ALVAC showed the opposite. A still-unpublished South African trial of a DNA vaccine suggested that it might have slightly delayed CD4 T-cell declines and the associated indication for ART.

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